MC3R

protein-coding

melanocortin 3 receptor, the group of Melanocortin receptors

Gene summary

This gene encodes a G-protein-coupled receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone that is expressed in tissues other than the adrenal cortex and melanocytes. This gene maps to the same region as the locus for benign neonatal epilepsy. Mice deficient for this gene have increased fat mass despite decreased food intake, suggesting a role for this gene product in the regulation of energy homeostasis. Mutations in this gene are associated with a susceptibility to obesity in humans. [provided by RefSeq, Jul 2008]

MANE transcript

NM_019888.3

Inheritance

ClinVar variants

P:1U:143B:56

Top phenotype

Obesity, severe, susceptibility to, 9

gnomAD constraint

pLI —, LoF o/e 1.5

Max pathogenic AF

—

Genomic locus

chr20:56,248,732-56,249,815

External References & Databases

Ensembl (ENSG00000124089)

Transcript & Mutation Effects

hg38 • Region Span ~1.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

body mass index quantitative trait locus 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044272

Submitter: PanelApp Australia

body mass index quantitative trait locus 9LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0044272

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Obesity, severe, susceptibility to, 9AD

Manifestation: Endocrine

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11889220; 18231126; 21047972

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MC3R variants in ClinVar

6 Conditions Cataloged

MC3R-related disorderTotal: 168

not providedTotal: 46

not specifiedTotal: 27

OBESITY (BMIQ9), SUSCEPTIBILITY TOTotal: 4

See casesTotal: 2

ObesityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019888.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	50 clinvar	2 clinvar	57
missense		1 clinvar	128 clinvar	2 clinvar	1 clinvar	132
nonsense			2 clinvar	1 clinvar		3
start loss						0
frameshift			8 clinvar			8
splice donor/acceptor (+/-2bp)						0
Total	0	1	143	53	3	200

Highest pathogenic variant AF is 0.00014514508

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019888.3	RefSeq	NP_063941.3	1	MANE Select
ENST00000243911.2	Ensembl	ENSP00000243911.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
Peptide GPCRs
GPCRs, Class A Rhodopsin-like
Signaling by GPCR
Signal Transduction

Biological Process

regulation of heart rate
G protein-coupled receptor signaling pathway
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
adenylate cyclase-activating G protein-coupled receptor signaling pathway
phospholipase C-activating G protein-coupled receptor signaling pathway

Molecular Function

melanocortin receptor activity
melanocyte-stimulating hormone receptor activity
protein binding
peptide hormone binding
neuropeptide binding

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000243911
Coding exons: 1
Length: 1084
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.140	201	195	1.03	0.0000129	2152
Missense (PolyPhen)		86	92.534	0.92939		1079
Synonymous	-0.193	91	88.7	1.03	0.00000729	660
Loss of Function	-1.14	9	6.00	1.50	2.66e-7	66

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain. {ECO:0000250|UniProtKB:P33033}.;

Intolerance Scores

LoFtool: 0.486
RVIS EVS: -0.4
RVIS percentile EVS: 26.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.807

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium